Research Endorsements
Professor Declan Murphy, Institute of Psychiatry, London
Brain anatomy of autism: a multi-centre study
There is increasing evidence that people with Autism spectrum disorder (ASD) have abnormalities in the way that some brain regions develop - and this may underpin some of the clinical symptoms typically expressed in people with the disorder. The cause of the differences in brain development is unknown - but it is most likely a combination of genetic and environmental factors. However, in people with ASD it is unknown how brain abnormalities are related to genes and/or the environment. Twin studies are a powerful approach for examining the genetic and environmental contribution(s) to brain differences. There has been only one prior twin study of brain anatomy in a group of people with ASD; and this reported preliminary evidence for ‘genetic’ effects on some brain differences, but ‘environmental’ effects on others. In addition there is a single case report. These were a valuable first steps. However brain scientists are increasingly aware that it is not just how big, or small, particular brain regions are that is crucial. Equally important is how brain regions are 'connected up' to each other. Nevertheless, nobody has examined how brain ‘connectivity’ is affected in twins (i.e. what causes brain regions to be ‘wired up’ differently in people with autism).
It has recently become possible to examine ‘connectivity’ using a technique called diffusion tensor magnetic resonance imaging (DT-MRI). This does not use any ionizing radiation, or injections. Thus our aim is to investigate the genetic and environmental determinants of brain anatomy and ‘connectivity’ in twins with and without ASD. We will use both conventional structural MRI and newer DT-MRI approaches to examine specific neural systems implicated in the disorder (e.g. language systems). The sample will be recruited from our large UK twin registers, and will bring together experts in autism, genetics, psychology, brain imaging, and behaviour. We anticipate that if our efforts are successful we will be able to initiate large-scale international twin studies using brain imaging. This study will help us understand more about the cause(s) of autism.
Professor Mark Johnson, University of London
UK Infant Siblings Project
Funding from Autism Speaks has encouraged me to extend my current research on typically developing babies to the study of babies and toddlers at elevated risk for developing autism. This extension of my research promises to reveal the earliest signs of autism during the first years of life. Detecting these early signs may allow us in the future to develop and test effective interventions that could, one day, potentially prevent the emergence of the full symptoms of autism. Since this kind of work requires large-scale studies of very many babies over several years, it can be difficult to obtain the necessary funding. The support and advocacy I have received from Autistica will be very important in this regard.
Read more about the research project on the BASIS website
Dr Payam Rezaie, The Open University
Examining Alterations in Cortical Neuronal Subpopulations and Synaptic Proteins in Autism
There is now a significant body of evidence which indicates that brain development is primarily affected in individuals with autism spectrum conditions. Neurological and psychiatric impairments typically become manifest before three years of age and autism can be diagnosed around this age. Nevertheless, the precise timing and nature of changes within the brain that lead to the spectrum of social and communicative deficits, and the stereotypical patterns and disturbances of behaviour manifest in individuals with autism, are not known. The aetiology of autism appears to be complex and multifactorial. The genetics underlying autism is highly complex and there does not appear to be a single gene component linked to autism. Instead, multiple genes and interactions between genetic as well as environmental factors are likely to be involved in the aetiopathogenesis of the condition. Structural and functional brain imaging studies have contributed significantly towards the clinical characterization of autism. These implicate various regions of the brain which function atypically in individuals with autism. However, even the most advanced imaging techniques cannot substitute for investigations that address brain tissues directly. Such neuropathological investigations, conducted on post-mortem material donated to established Tissue Banks, such as those associated with the Autism Tissue Program (ATP) in the US, and the MRC London Brain Bank for Neurodegenerative Diseases (LBBND) in the UK, offer a unique perspective to determine the neurobiology of autism, from the cellular level through to subcellular compartments and genes. Co-ordinated and systematic neuropathological analyses offer the most direct route to obtaining answers as to the neurobiological causes and bases for autism spectrum conditions. Data from such studies in turn impact directly on attempts to generate relevant experimental models to develop effective therapeutic interventions.
Within the Neuropathology Research Laboratory (Department of Biological Sciences, the Open University), we have been working on two projects funded by Autistica that examine distinct aspects of the neurobiology of autism. In the first of these, “Assessment of the glial response within the cerebral cortex in autism”, we have been investigating alterations in the responses of astrocytes and microglia (glial cells) within multiple brain areas known to be functionally affected in autism. Disturbances in the function of these cells have adverse consequences on the activity of neurons and vice versa. Furthermore, neuro-immune interactions within the brain are governed locally by networks of these resident glial cells, and their activation is known to parallel ongoing pathology. We have found significant alterations in astrocyte responses within the cerebral cortex of individuals with autism. Our findings have been presented at three National Meetings (107th Meeting of the British Neuropathological Society, 11-13 January 2006; 19th National Meeting of the British Neuroscience Association, 1-4 April 2007; National Conference on Autism Research in the UK - from diagnosis to intervention, 11-12 May 2007), and we are currently submitting these results for publication in peer-reviewed scientific journals. Our second, ongoing study is “Examining alterations in cortical neuronal subpopulations and synaptic proteins in autism”. This study aims to systematically investigate changes in the profiles of subpopulations of neurons (interneurons and pyramidal cell neurons) within the cortical grey matter, using computerised image analysis of sectioned material derived from two cohorts of cases (from the US, through the Autism Tissue Program, and in the UK (MRC LBBND). The study will determine for the first time which, if any, of these neuronal subpopulations are altered within functionally-defined regions of the brain in individuals with autism. The analysis will further determine whether the expression of specific proteins at junctions between neurons (synaptic proteins), are also disturbed within these same brain areas.
Both of these research projects have built on extended and ongoing collaborations with Dr. Christoph Schmitz (Maastricht University) in the Netherlands, and Drs. Jane Pickett (ATP) and Jerzy Wegiel (Institute for Basic Research in Developmental Disorders) in the US, as part of the international collaborative research effort on the ATP Brain Atlas Project. Collaborations have also been established with Drs. Safa Al-Sarraj (MRC LBBND), Sabine Landau (Institute of Psychiatry, London) and Andrew Dean (Addenbrooke’s Hospital, Cambridge) here in the UK. We are deeply indebted to the brain tissue donors and their families, and we gratefully acknowledge the Autism Tissue Program, USA, Harvard Brain Tissue Resource Centre, Belmont, USA, University of Maryland Brain and Tissue Bank for Developmental Disorders, Baltimore, USA, and the MRC London Brain bank for Neurodegnerative Diseases, Institute of Psychiatry, London, and the Cambridge Brain and Tissue Bank, Addenbrooke’s Hospital, Cambridge, as sources of post-mortem tissues.
Support from Autistica, has enabled us to address these fundamental questions, with the central aim of advancing our understanding of the neurobiology of autism. Data from these studies will form an essential foundation on which to further develop, and appropriately investigate therapeutic interventions for autism, experimentally. The support has further enabled us to capitalise on the expertise offered through establishing and maintaining collaborations with neuroscientists united through their dedication and commitment to uncovering the underlying causes of autism. The combination of these investigations will enable us for the first time, to form a more comprehensive picture of cellular alterations within the brain in patients affected with autism. The ultimate goal is to integrate the separate investigations targeting the different aspects of the neurobiology of autism (glial, neuronal and synaptic), in a systematic and coherent manner in order to gain clearer insights into the cellular and cytoarchitectural alterations affecting the brain in autism. This knowledge is prerequisite to the development of appropriate biomedical treatments that lead to improving the quality of life of individuals who are affected, and ultimately towards providing a cure for, and prevention of, autistic conditions. In these respects our research is fully in line with the remits that are central to the scientific mission of Autistica, and we are grateful for the support made available in the pursuit of these objectives.
Dr Payam Rezaie PhD, Neuropathology Research Laboratory, Department of Biological Sciences, Faculty of Science, The Open University, Walton Hall, Milton Keynes, MK7 6AA UK.
Tel: +44 (0) 1908 858197 Fax: +44 (0) 1908 654167 Email Professor Rezaie
